2. Academic Validation
  3. Current progress and novel strategies that target CDK12 for drug discovery

Current progress and novel strategies that target CDK12 for drug discovery

  • Eur J Med Chem. 2022 Oct 5:240:114603. doi: 10.1016/j.ejmech.2022.114603.
Peng Lei 1,  Jifa Zhang 2,  Peiyu Liao 3,  Changyu Ren 4,  Jiaxing Wang 5,  Yuxi Wang 6
Affiliations

Affiliations

  • 1 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China.
  • 3 School of Pharmacy, Chengdu Medical College, Chengdu, 610500, Sichuan, China.
  • 4 Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, 611130, Sichuan, China.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
  • 6 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Tianfu Jincheng Laboratory, Chengdu, 610041, Sichuan, China. Electronic address: yuxiwang@scu.edu.cn.
PMID: 35868123 DOI: 10.1016/j.ejmech.2022.114603
Abstract

CDK12 is a cyclin-dependent kinase that plays critical roles in DNA replication, transcription, mRNA splicing, and DNA damage repair. CDK12 genomic changes, including mutation, amplification, deletion, and fusion, lead to various cancers, such as colorectal Cancer, gastric Cancer, and ovarian Cancer. An increasing number of CDK12 inhibitors have been reported since CDK12 was identified as a biomarker and Cancer therapeutic target. A major challenge lies in that CDK12 and CDK13 share highly similar sequences, which leads to great difficulties in the development of highly selective CDK12 inhibitors. In recent years, great efforts were made in developing selective CDK12 blockers. Techniques including PROTAC and molecular glue degraders were also applied to facilitate their development. Also, the drug combination strategy of CDK12 small molecule inhibitors were studied. This review discusses the latest studies on CDK12 inhibitors and analyzes their structure-activity relationships, shedding light on their further development.

Keywords

CDK12; Cancer; Drug combination; Inhibitors.

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